PROJECT SUMMARY Immunopharmacotherapeutics, also called addiction vaccines, represent an emerging treatment strategy for the treatment of nicotine dependence. These addiction vaccines induce the production of antibodies that bind to nicotine molecules and sequester them in the periphery in order to mitigate their rewarding effects. While several phase II and III clinical trials have been conducted with nicotine vaccines, none of the studied injectable preparations have resulted in improved rates of smoking cessation across all patients. However, further inspection of the data has presented cause for optimism. While none of the tested vaccines induced a robust immune response in all treated subjects, those patients who were able to mount the most robust immune responses were found to have a higher chance of successfully quitting. These observations indicate that while the principles behind the use of nicotine vaccines are valid, improved administration tactics are needed to improve the overall efficacy and dosing flexibility of nicotine vaccination strategies. Thus, we aim to generate a nicotine vaccine that is suitable for pulmonary administration using liposome-conjugated haptens. With this formulation in hand, the ability of this pulmonary nicotine vaccine to generate a soluble IgA-biased immune response and decrease nicotine delivery to the brain will be measured. Next, a model of nicotine dependence arising from chronic intermittent exposure to nicotine vapor will be used to measure the ability of this liposomal vaccine to diminish symptoms and place aversion due to nicotine withdrawal. Finally, the anatomical distribution of the liposomal particles in mouse lungs will be assessed ex vivo following aerosolization using a radiolabelled tracer. Overall, it is hypothesized that pulmonary administration of a liposomal vaccine will lead to vigorous immune and behavioural responses, and that this formulation will be suitable for aerosol administration. Successful demonstration of these characteristics would provide a proof-of-principle that pulmonary delivery of nicotine vaccines could enable the application of individualized dosing regimens via repeated aerosol self- administration. If provided alongside nebulized nicotine, such a mechanism of vaccine dosing could potentially even arise naturally, using biofeedback from continued nicotine use. This would represent a significant breakthrough for the field by removing inter-individual variability as an obstacle to the achievement of population-wide efficacy for smoking cessation.